PKC Inhibitor AEB071 Demonstrates Pre-Clinical Activity In Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4187-4187
Author(s):  
Dalia ElGamal ◽  
Yiming Zhong ◽  
Katie Williams ◽  
Chia-Hsien Wu ◽  
Ching-Shih Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Survival ◽  
Stromal Cells ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Pkc Inhibitor ◽  
Pkc Β

Abstract Targeting B-cell receptor (BCR) downstream pathways is of therapeutic importance in eradicating chronic lymphocytic leukemia (CLL) cells. Members of the protein kinase C (PKC) family play an important role in B-cell activation. PKC-β has recently been shown to be over-expressed in CLL and essential to CLL development in the TCL1 mouse model. Mice deficient in PKC-β exhibit a survival defect in response to BCR stimulation, correlating with an inability to induce the NF-κB-dependent anti-apoptotic proteins as Bcl-xL and A1. Moreover, PKC-β-dependent activation of NF-κB in stromal cells is pivotal for the survival of B-CLL cells in vivo; wherein PKC-β inhibition was shown to prevent microenvironment protection of CLL. Additionally, PKC-β lies downstream of PLC-γ2 where activating mutations have been noted in BTK (ibrutinib) resistant patients, which conveys a potential mechanism to target resistance related to mutations in this target protein. Therefore exploration of a PCK-β inhibitor in CLL is highly justified and innovative. Sotrastaurin (AEB071) is an orally administered potent inhibitor of classical and novel PKC isotypes; with strong and specific activity on PKC-α, PKC-β and PKC-θ and lesser activity on PKC-δ, PKC-ε, and PKC-η. Pre-clinically, AEB071 has demonstrated in vivo pre-clinical activity in activated B-cell diffuse large B-cell lymphoma (DLBCL) models and is currently being tested for efficacy in CD79b mutated DLBCL. Since PKC-β is indispensable for BCR-induced NF-κB activation and B-cell survival, herein we evaluate the impact of AEB071 on CLL cell survival as a promising therapeutic to target this pathway. Our preliminary work demonstrated that AEB071 was markedly cytotoxic to CLL cells in a dose-dependent (≤6.25uM, p<0.001) and time-dependent manner (p=0.011) as measured by MTS analysis. In a whole blood assay, AEB071 exhibits a retained selective cytotoxicity against tumor cells with a modest reduction in B-CLL cells whereas no effect on T-cells or natural killer cells was detected in CLL patient samples. Notably, upon treatment of blood from healthy subjects, AEB071 showed no toxic effects on normal B-cells, T-cells and natural killer cells. AEB071 inhibits CPG-induced survival of CLL cells in vitro (p<0.01), and effectively blocks the protection induced by soluble factors such as CD40L, IL-4, and TNF (p<0.01), which are known to reduce the spontaneous apoptosis associated with CLL cells. Similar effects were observed with stromal cell contact; wherein AEB071 showed enhanced cytotoxic potency on CLL cells under co-culture conditions with stromal cells compared to CLL alone (p<0.05). Additionally, AEB071 attenuated anti-IgM-induced survival of CLL cells with a modest induction of apoptosis (p<0.001). Furthermore, treatment of PMA- or BCR-activated CLL cells with AEB071 could effectively abrogate downstream survival pathways including ERK1/2, p38MAPK, AKT, GSK3β, and NF-κB as revealed by immunoblot analysis. Collectively, this data indicate that therapeutic strategies to inhibit PKC-β have the potential to disrupt signaling from the microenvironment that lead to in vivo CLL cell survival and potentially drug resistance. Current studies are ongoing to evaluate the in vivo tolerability and therapeutic efficacy of AEB071 in the Eμ-TCL1 transgenic mouse model of CLL. In conclusion, PKC-β represents an innovative target for CLL and therefore, future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients may be warranted. Disclosures: No relevant conflicts of interest to declare.

The Plant-Derived Agent Silvestrol Has B-Cell Selective Activity In Vitro in Chronic Lymphocytic Leukemia Patient Cells and In Vivo in the Tcl-1 Mouse Model of CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3123-3123 ◽  
Author(s):  
David M. Lucas ◽  
Ryan B. Edwards ◽  
Michael D. De Lay ◽  
Derek A. West ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphocytic Leukemia ◽  
Pathological Examination ◽  
Cell Percentage ◽  
Leukocyte Counts

Abstract Chronic Lymphocytic Leukemia (CLL) is an incurable disease with limited therapeutic options, especially for high-risk populations such as the del(17p13) patient subset. Currently available therapies for CLL, even if effective, can have significant detrimental effects on remaining T cells, leaving patients at risk of potentially lethal opportunistic infections. New agents with unique mechanisms of action, independence of key resistance pathways, and selectivity for tumor cells are crucial to make an impact on patient survival. Silvestrol, a structurally unique compound isolated from the plant genus Aglaia, exhibited potent activity against several tumor cell lines and moderate in vivo activity in the P388 mouse leukemia model (J. Org. Chem. 2004, 69:3350; ibid. 69:6156). Based on these results, we tested silvestrol against tumor cells obtained from CLL patients. The LC50 (concentration lethal to 50% of cells relative to untreated control) of silvestrol was 6.5 nM at 72 hours by MTT assay. We performed assays to determine CLL patient cell viability at 72 hours with or without drug washout at various times. In these studies, silvestrol showed up to 50% killing at 72 hours with only a four hour exposure, and reached maximum efficacy with a 24 hour exposure. Silvestrol was similarly effective against cells from CLL patients with or without del(17p13). Furthermore, there was no significant difference in silvestrol-mediated cytotoxicity between lymphoblastic cells with a ten-fold overexpression of Bcl-2 relative to control cells. In MTT assays using isolated CD3+ or CD19+ cells, and in whole blood from healthy volunteers and CLL patients, silvestrol demonstrated substantially more cytotoxicity toward B cells than T cells. We then tested silvestrol using Tcl-1 transgenic mice, which are initially normal but develop a slow-progressing B cell leukemia very similar to human CLL. Lymphocytes obtained from spleens of Tcl-1 mice with leukemia were incubated ex vivo with 80 nM silvestrol and analyzed by flow cytometry. Silvestrol produced an 88% reduction in the B cell percentage after 24 hours with no negative effect on the T cell percentage (8% increase), in contrast to 1 μM fludarabine, which affected both B cell (22% reduction) and T cell (14% reduction) subsets. Non-leukemic mice of the Tcl-1 background strain were treated with 1.0, 1.5 and 2.5 mg/kg/day silvestrol for 5 days to determine a tolerable dose. Three of five mice treated with 2.5 mg/kg/day died at the beginning of the second week of treatment. However, none of the animals treated at 1.0 or 1.5 mg/kg showed signs of toxicity or weight loss even after two full weeks of treatment and were normal at pathological examination. Tcl-1 mice with evidence of leukemia as determined by elevated leukocyte counts and enlarged spleens were then treated with silvestrol at 1.5 mg/kg/day × 5 days for two weeks. Treated mice experienced decreased overall leukocyte counts relative to vehicle controls. Furthermore, CD19+ cell numbers and percentages diminished substantially while the T cells were only mildly affected. Additional leukemic Tcl-1 mice are currently being treated and studies are underway examining the mechanism of action of silvestrol in CLL cells.

Chronic Lymphocytic Leukemia-Exosomes Switch Endothelial and Mesenchymal Stromal Cells into Cancer-Associated Fibroblasts to Sustain Leukemic Cell Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2927-2927 ◽  
Author(s):  
Jerome Paggetti ◽  
Franziska Haderk ◽  
Martina Seiffert ◽  
Bassam Janji ◽  
Yeoun Jin Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
B Lymphocytes ◽  
Stromal Cells ◽  
Leukemic Cell ◽  
Lymphoid Organs ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells

Abstract Chronic lymphocytic leukemia (CLL), the most common hematologic malignancy in Western countries, is mostly affecting the elderly over 65 year-old. CLL is characterized by the accumulation of mature but non-functional B lymphocytes of clonal origin in the blood and the primary lymphoid organs. CLL was previously considered as a relatively static disease resulting from the accumulation of apoptosis-resistant but quiescent B lymphocytes. However, recent studies using heavy water labeling indicated that CLL is in fact a very dynamic disease with alternation of proliferation phases and peripheral circulation. A focus on the trafficking of CLL cells in vivo has shown that leukemic cells circulate between the blood and the lymphoid organs but have a preference for the bone marrow. Recent next-generation sequencing of CLL cells indicated the presence of different genetic subclones. This intraclonal heterogeneity observed in CLL subpopulations may be in part determined by the interactions that leukemic cells entertain with their microenvironment when B cells migrate into the lymph nodes and the bone marrow. Indeed, tumor-stroma interactions are not only providing signals necessary for leukemic cells survival but may also influence the clonal architecture and evolution. One of these interactions involves CLL-derived exosomes. Here, we show that CLL-exosomes efficiently transfer nucleic acids, including functional microRNAs, and proteins, including MHC-Class II molecules and B-cell specific proteins, to bone marrow mesenchymal stem cells and endothelial cells. CLL-exosomes also activate signaling pathways, including PI3K and NF-κB pathways, in these stromal cells. As a consequence, gene expression is strongly modified indicating a switch towards a cancer-associated fibroblast phenotype. Functionally, exosome-stimulated stromal cells show a striking actin cytoskeleton remodeling characterized by the formation of stress fibers, and enhanced proliferation, motility and angiogenic properties. We also identified several proteins synthesized and secreted by stromal cells that promote leukemic cell adhesion and survival ex vivo. To confirm the involvement of CLL-exosomes in CLL pathology in vivo, MEC-1-eGFP cells were subcutaneously injected into immunocompromised NSG mice together with CLL-exosomes. We observed a significant increase in tumor size and a reduction in survival of exosome-treated animals. Flow cytometry analysis of selected organs indicated an enrichment in leukemic cells in the kidney, providing a potential explanation to the renal failures observed in CLL patients. In conclusion, the communication between CLL cells and stromal cells may be a critical factor influencing CLL progression by promoting leukemic cell survival. This study demonstrates the crucial role of exosomes as mediators of the communication between leukemic cells and their microenvironment. Exosomes could thus represent a suitable target for therapeutic intervention in CLL. Disclosures No relevant conflicts of interest to declare.

scholarly journals LNA-mediated anti–miR-155 silencing in low-grade B-cell lymphomas

Blood ◽  
2012 ◽  
Vol 120 (8) ◽  
pp. 1678-1686 ◽  
Author(s):  
Yong Zhang ◽  
Aldo M. Roccaro ◽  
Christopher Rombaoa ◽  
Ludmilla Flores ◽  
Susanna Obad ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Growth ◽  
B Cell ◽  
Stromal Cells ◽  
Leukemia Cell ◽  
Lymphocytic Leukemia ◽  
Locked Nucleic Acid ◽  
Low Grade ◽  
Seed Region

Abstract miR-155 acts as an oncogenic miR in B-cell lymphoproliferative disorders, including Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia, and is therefore a potential target for therapeutic intervention. However, efficient targeting of miRs in tumor cells in vivo remains a significant challenge for the development of miR-155–based therapeutics for the treatment of B-cell malignancies. In the present study, we show that an 8-mer locked nucleic acid anti–miR-155 oligonucleotide targeting the seed region of miR-155 inhibits WM and chronic lymphocytic leukemia cell proliferation in vitro. Moreover, anti–miR-155 delivered systemically showed uptake in the BM CD19+ cells of WM-engrafted mice, resulting in the up-regulation of several miR-155 target mRNAs in these cells, and decreased tumor growth significantly in vivo. We also found miR-155 levels to be elevated in stromal cells from WM patients compared with control samples. Interestingly, stromal cells from miR-155–knockout mice led to significant inhibition of WM tumor growth, indicating that miR-155 may also contribute to WM proliferation through BM microenvironmental cells. The results of the present study highlight the therapeutic potential of anti–miR-155–mediated inhibition of miR-155 in the treatment of WM.

scholarly journals The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1182-1189 ◽  
Author(s):  
Sabine Ponader ◽  
Shih-Shih Chen ◽  
Joseph J. Buggy ◽  
Kumudha Balakrishnan ◽  
Varsha Gandhi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Survival ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Targeted Agent

Abstract B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.

The PI3 Kinase δ Inhibitor, CAL-101 (GS-1101), Inhibits Chronic Lymphocytic Leukemia (CLL) Cell Survival in Endothelial and Marrow Stromal Cell Co-Cultures.

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1769-1769 ◽  
Author(s):  
Stefania Fiorcari ◽  
Wells S Brown ◽  
Bradley W McIntyre ◽  
Susan O'Brien ◽  
Mariela Sivina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Survival ◽  
Stromal Cells ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Spontaneous Apoptosis ◽  
Cell Protection ◽  
Survival Signals

Abstract Abstract 1769 CLL cells are characterized by their ability to resist apoptosis in vivo, but in vitro they undergo spontaneous apoptosis. This suggests that interactions between CLL cells and accessory cells in the tissue microenvironments, such as mesenchymal stromal cells (MSC), nurselike cells (NLC), T-cells, and endothelial cells are critical for maintaining CLL cell survival. CLL cells display constitutive PI3K pathway activation, presumable due to CLL interactions with the microenvironment. CAL-101 is a potent and selective inhibitor of the p110d PI3K isoform and has shown promising clinical activity in chronic lymphocytic leukemia (CLL) in early stage clinical trials. Here, we investigated the ability of CAL-101 to disrupt interactions between CLL and endothelial cells (EC) or bone marrow stromal cells (BMSC). We tested two EC lines human umbilical vein endothelial cells (HUVEC) and UV-2 mouse vascular endothelial cells, and two BMSC lines, stroma-NKtert derived from human bone marrow, and KUSA-H1, a murine BMSC line. CLL cells were cultured for 72h in presence or absence of EC or BMSC. Fig A displays mean (±SEM) CLL cell viabilities of cells from 7 different patients. We found that both, EC and BMSC rescue CLL cells from spontaneous apoptosis with significantly higher CLL cell viabilities in the presence of EC and BMSC (*P< 0.05; **P< 0.01). For example, after 48h significantly higher CLL cell viabilities were noticed with HUVEC (53.2%±4.3%, p<0.05,), UV2 (61.8%±5.3%, p<0.01), stroma-NKtert (96.7%±5.3%, p<0.01) and KUSA-H1 (93.7%±0.95%, p<0.01), when compared to CLL cultured in medium alone (37.5%±4.1%). To test the effects of CAL-101 on EC- and BMSC-mediated CLL cell protection, CLL cells were cultured on ECs or BMSCs in presence or absence of CAL-101 (0.5μM and 5μM), and CLL cell viabilities were assessed at 24h, 48h and 72h. Viabilities of CAL-101 treated samples were normalized to the viabilities of control samples at the respective timepoints (100%). Fig B depicts the mean relative viabilities of CLL cells co-culture with ECs or BMCSs in presence of 5μM CAL-101, compared to CLL cells in the absence of CAL-101. We found a significant reduction of the viability of CLL cells in co-culture with EC and BMSC with both concentrations of CAL-101 (*P< 0.05; **P< 0.01; n=7). These data demonstrate that marrow stromal and endothelial cells both support the viability and protect CLL cells from apoptosis. When comparing BMSC with EC, we noticed that BMSC were more effective than EC in protecting CLL cells, which may explain why the marrow is a preferred site for residual disease and relapses in patients with CLL. CAL-101 can overcome both, BMSC- and EC-mediated CLL cell protection, indicating that CAL-101 inhibits BMSC- and EC-derived pro-survival signals. Ongoing experiments investigate the role of adhesion molecules on BMSC- and EC-derived survival signals and CLL cell adhesion to BMSC versus EC, and how adhesion molecule function is affected by CAL-101. These studies will give us better insight into the mechanism of action of this interesting new drug. Disclosures: O'Brien: Gilead: Consultancy, Research Support. Lannutti:Gilead Sciences: Employment.

Mir-155 Contributed to Chronic Lymphocytic Leukemia Survival by Modulation of BCR-Signalling

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 620-620
Author(s):  
Liguang Chen ◽  
Bing Cui ◽  
George Chen ◽  
Michelle Salcedo ◽  
Carlo M. Croce ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Survival ◽  
Stromal Cells ◽  
Initial Therapy ◽  
Lymphocytic Leukemia ◽  
Expression Levels ◽  
Bcr Signaling ◽  
Median Level

Abstract Abstract 620 The microRNA miR-155 is encoded within the B-cell integration cluster bic, which is a frequent integration site for avian leucosis virus. This microRNA is over-expressed in certain B cell lymphomas, including chronic lymphocytic leukemia (CLL), suggesting miR-155 contributes to lymphoma development. Consistent with this are observations that mice made transgenic for miR-155 under a B-cell-specific promoter develop pre-B cell lymphomas. One of the target genes regulated by miR-155 is SHIP-1, a phosphatase that plays a critical role in down-modulating B-cell receptor (BCR) signaling, which appears to provide a growth and/or survival stimulus for CLL B cells. To test for this, we examined for relationships between the CLL-cell expression of miR-155, SHIP-1, magnitude of BCR-signaling, and time from diagnosis to initial therapy (TFS) in 33 pts with CLL. The relative level of miR-155 was determined by real-time PCR. SHIP-1 protein was determined by flow cytometry and immunoblot analyses. We noted variations in expression levels of miR-155 among patient samples studied. CLL cells that expressed levels of miR-155 higher than the median level of miR-155 for all patients studied had significantly lower expression levels of SHIP-1 protein than CLL cells that expressed levels of miR-155 lower than the median level of miR-155 had (7.0 ± 0.2 vs. 8.3 ± 0.47, mean ± SEM, P<0.05). CLL B cells were stimulated with anti-μ or control Ig and then examined for relative protein phosphorylation and calcium influx. CLL cases were segregated into groups with high-BCR signaling versus low BCR-signaling based on their responses to anti-μ stimulation. We found that CLL cells with high-BCR signaling expressed significantly higher levels of miR-155 (1.54 ± 0.22) than did CLL cells with low-BCR signaling (0.90 ± 0.13, p<0.05). CLL cells with high BCR-signaling had significantly lower amounts of SHIP-1 protein (7.1 ± 0.39) than did CLL cells with low BCR-signaling (9.12 ± 0.7, p<0.05). Moreover, Kaplan-Meier survival analysis revealed an association between higher expression levels or miR-155 and shorter survival times from diagnosis to initial therapy (TFS) (P<0.05). CLL patients with greater miR-155 expression had a median TFS of 25.9 months that was significantly shorter than the median TFS of 112.8 months for patients with low miR-155 expression. To further investigate its function role, CLL cells were transfected with miR155 mimic or a miR-155 inhibitor and examined for SHIP-1 expression, BCR signaling, and cell survival, with or without stromal cells. Introduction of miR-155 to CLL cells that had low expression levels of miR-155 significantly reduced SHIP-1 protein expression, enhanced BCR signaling and improved cell survival relative to that of mock transfect CLL cells or CLL cells tranfected with micro RNA. Conversely, transfection of CLL cells that had high expression levels of miR-155 with miR-155 inhibitor resulted in significantly increased SHIP-1 expression, reduced BCR signaling, and poor survival than mock transfected CLL cells. Moreover, transfection of miR-155 inhibitor significantly reduced the capacity of stromal cells to enhance CLL cell survival. We found that the viability of cells transfected with miR-155 inhibitor was significantly lower than that noted for cells transfected with control miRs when cocultured with stromal cells. These results demonstrate that expression of miR-155 can modulate CLL expression of SHIP-1, CLL cell BCR signaling, and survival. Disclosures: No relevant conflicts of interest to declare.

The influential T cell in B-cell neoplasms.

1983 ◽  
Vol 1 (12) ◽  
pp. 810-816 ◽  
Author(s):  
N E Kay ◽  
M M Oken ◽  
R T Perri
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Clinical Effects ◽  
B Cell Malignancies

Investigations of human B-cell malignancies have generally focused on the monoclonal B-cell populations. Until recently there has been little emphasis on the thymus (T) lymphocyte in these disorders. Current studies, however, suggest that quantitative and qualitative disorders of T cells are generally seen both in chronic lymphocytic leukemia and in multiple myeloma. This review will focus on two major concepts. First, it will define the quantitative and functional T-cell abnormalities in B-cell malignancies including evidence suggesting a causal link between the T-cell abnormalities and certain observed disease manifestations in chronic lymphocytic leukemia and multiple myeloma. Secondly, it will review data demonstrating that these T cells may be influenced by in vivo and in vitro manipulations and will outline some of the possible resultant clinical effects.

Novel Treatments for Chronic Lymphocytic Leukemia and Moving Forward

2014 ◽  
pp. e317-e325 ◽  
Author(s):  
Jennifer R. Brown ◽  
David L. Porter ◽  
Susan M. O'Brien
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Novel Agents ◽  
Novel Therapies ◽  
B Cell Malignancies ◽  
Short Period

The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.

B-cell receptor signaling in chronic lymphocytic leukemia

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4313-4320 ◽  
Author(s):  
Freda K. Stevenson ◽  
Sergey Krysov ◽  
Andrew J. Davies ◽  
Andrew J. Steele ◽  
Graham Packham
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Variable Regions ◽  
Bcr Signaling

Abstract The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach.

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